Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases.
Kamata H et al.
Cell. 2005 Mar 11; 120(5):649-661
https://doi.org/10.1016/j.cell.2004.12.041PMID: 15766528TNFalpha is a pleiotropic cytokine that induces either cell proliferation or cell death. Inhibition of NF-kappaB activation increases susceptibility to TNFalpha-induced death, concurrent with sustained JNK activation, an important contributor to the death response. Sustained JNK activation in NF-kappaB-deficient cells was suggested to depend on reactive oxygen species (ROS), but how ROS affect JNK activation was unclear. We now show that TNFalpha-induced ROS, whose accumulation is suppressed by mitochondrial superoxide dismutase, cause oxidation and inhibition of JNK-inactivating phosphatases by converting their catalytic cysteine to sulfenic acid. This results in sustained JNK activation, which is required for cytochrome c release and caspase 3 cleavage, as well as necrotic cell death. Treatment of cells or experimental animals with an antioxidant prevents H(2)O(2) accumulation, JNK phosphatase oxidation, sustained JNK activity, and both forms of cell death. Antioxidant treatment also prevents TNFalpha-mediated fulminant liver failure without affecting liver regeneration.
- Kamata H 1,
- Honda S ,
- Maeda S ,
- Chang L ,
- Hirata H ,
- Karin M
Affiliations
- 1 Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
This work was supported by:
NIEHS NIH HHS, United States
GrantID: ES06376
NIEHS NIH HHS, United States
GrantID: ES04151
NIAID NIH HHS, United States
GrantID: AI43477
NIEHS NIH HHS, United States
GrantID: 5P42 ES10337